Abstract More than half of end-stage renal disease (ESRD) patients on hemodialysis (HD) report debilitating pain, which is associated with poor health-related quality of life, increased hospitalizations and mortality. Often, their pain is managed poorly and ineffectively. Additionally the high prevalence of opioid use in these patients increases their risk of hospitalizations and mortality. The overall goal of the proposed Pain Reduction and Opioid Medication Safety in ESRD (PROMISE) study is to improve safety of opioid use and pain management in HD patients using a Type I effectiveness-implementation hybrid design. In this multi-site randomized controlled trial of 560 HD patients from the Hemodialysis Opioid Prescription Effort (HOPE) Consortium, we will use a 2x2 factorial design to examine the effectiveness of two separate 9- month evidence-based interventions: 1) Opioid Tapering Management (OTM), and 2) Behavioral Pain Management (BPM). The OTM intervention consists of a collaborative care model in which a nurse care manager works closely with patients, primary care physicians (PCPs) and dialysis teams to develop and manage an individualized approach for analgesic optimization with focus on opioid tapering or transition to buprenorphine in all patients after consensual agreement with patient and PCP. The BPM combines two evidence based treatments - Acceptance and Commitment Therapy (ACT) for pain and Cognitive Behavioral Therapy (CBT) for co-existing depression/anxiety (when present) and is delivered via telemedicine during HD. The control condition not assigned to either OTM or BPM will be usual care and have the option to receive ACT at the end of 12 months. We will examine the effectiveness of OTM (versus no OTM, Aim 1) and BPM (versus no BPM, Aim 2) over 9-months for reducing opioid use (primary outcome) and improving pain severity (secondary outcome) in HD patients on chronic opioids. The implementation goal will take advantage of the diverse patient, provider and organizational settings in the HOPE Consortium to evaluate process outcomes for from multiple stakeholders (Aim 3). Our study combines novel tools and resources to decrease opioid related morbidity, address the opioid epidemic, alleviate pain for HD patients, in addition to providing insights to inform integration of these interventions into dialysis practice and policy.